Although age is the largest single risk factor for cancer, the molecular genetic basis underlying the interrelationship between cancer and aging remains largely unknown. Filling this gap in knowledge is important for understanding both cancer and aging. BubR1, a core mitotic checkpoint component that regulates proper chromosome segregation, has emerged as a key determinant of both cancer and aging. Mutant mice carrying BubR1 hypomorphic alleles (BubR1H/H mice) that produce low amounts of the protein accumulate aneuploid cells and are susceptible to tumors. These animals also develop various progeroid and early aging-related phenotypes, including short lifespan, growth retardation, cataracts, sarcopenia, subdermal fat loss, reduced dermal thickness, and impaired wound healing. Furthermore, mutations in BubR1 have been associated with mosaic variegated aneuploidy (MVA), a rare human syndrome that is characterized by aneuploidization, cancer, and several progeroid traits, many of which overlap with those seen in BubR1H/H mice. Importantly, BubR1 abundance declines in various mouse tissues with chronological aging. A ubiquitously expressed BubR1 transgene that prevents this decline preserves chromosomal integrity, reduces tumorigenesis, extends lifespan, and delays age-related deterioration of several tissues. The objective of this application is to resolve the molecular pathway governed by BubR1 and to determine how changes in BubR1 abundance alter the rate with which cancer and age-related pathologies develop. Based on persuasive preliminary data we hypothesize that uncontrolled APC/CCdc20 E3 ubiquitin ligase activity that results from BubR1 insufficiency plays a central role in cancer susceptibility and premature aging, and that sustained levels of BubR1 attenuate the development of cancer and age-related disorders by maintaining proper control of APC/CCdc20. We will test this hypothesis by pursuing three specific aims. In the first aim, we will determine how mechanistically BubR1 over- expression protects against cancer and aging. In the second aim, we will determine how uncontrolled APC/CCdc20 activity drives cancer and premature aging. In the third aim, we will establish the role of BubR1 kinase activity in controlling APC/CCdc20 activity, cancer and aging. The expected overall impact of the proposed work is that it will fundamentally advance our mechanistic understanding of a prominent mitotic check- point protein implicated in two major human health problems, cancer and aging, and will provide insight into how contrasting changes in BubR1 abundance alter the rate with which cancer and age-related pathologies develop. This knowledge will pave the way towards transformative clinical interventions for treating or preventing a broad spectrum of human cancers and age-related diseases that limit healthspan, in addition to conceptually advancing the fields of mitosis, cancer and aging.